Most cancer-related deaths are attributable to metastatic disease, a multistep process that includes invasion, angiogenesis, intravasation, extravasation, colonization and growth. Despite advances in our understanding of cancer, few therapeutics to prevent or treat metastases are currently available. The focus of my dissertation research has been to investigate the molecular and cellular events that lead to cancer metastasis, using breast cancer as a model, and to elucidate factors that may promote or suppress this process.
Here, I investigate the effects of GATA3 on tumor cell differentiation and metastasis. I show that GATA3 inhibits lung metastasis through miR-29b, a microRNA that promotes differentiation and targets pro-metastatic regulators of the tumor environment for degradation. GATA3 also inhibits bone metastasis, likely through suppression of osteopontin. In addition, I present a preliminary GATA3 ChIP-seq dataset performed in breast cancer cells to uncover novel GATA3 targets.
Because microRNAs are generally down-regulated in cancer, I investigate the consequences of globally decreasing microRNAs using a conditional knockout for Dgcr8. I show that Dgcr8 controls cellular differentiation and branching morphogenesis in both normal and tumorigenic mammary epithelial cells. In contrast to other cancer studies on DICER, Dgcr8 deletion in MMTV-PyMT tumors impairs growth and metastasis.
The microenvironment at distant metastatic sites is altered by the primary tumor. I describe preliminary work on the metastatic lung niche in MMTV-PyMT mice that is established early during tumor progression and associated with increases in pro-inflammatory mediators. We find increased number of MMP9-expressing CD11b+Gr1+ myeloid cells that cluster around lung metastases, which may promote colonization and growth.
Finally, I describe two projects investigating the roles of novel metastasis-promoting genes, Zeppo1 and Znf217. Both these genes lie in commonly amplified regions in poor-prognostic breast cancers. Zeppo1 promotes metastasis by repressing E-cadherin expression and promoting a p120-catenin isoform switch while Znf217 promotes mesenchymal marker expression and chemotherapy resistance. I also describe the development of the tetrapod quantum dot, a novel tool to study cell-generated forces and characterize novel FVB/n cell lines that I've generated from primary mouse breast tumors, which will serve as a resource for our lab and others.